Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood(Toxicology)

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Bromate, an inorganic oxyhalide disinfection by-product, is known to cause kidney damage, haemolysis and methaemoglobinemia. In potassium bromate (KBrO_3)-treated mice (1.2 mmol/kg), elevation of methaemoglobin (MetHb) concentration in blood was observed simultaneously with an elevation of the NO concentration and attenuation of glutathione peroxidase (GPx) activity. Renal oxidative stress and kidney damage were also confirmed in the KBrO_3-treated mice. A pre-administered GPx-mimic ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) dose-dependently diminished the KBrO_3-induced changes in MetHb concentration and GPx activity. Renal oxidative stress and kidney damage caused by the KBrO_3 administration were also dose-dependently suppressed by ebselen. On the other hand, ebselen did not suppress the KBrO_3-induced elevation of the NO concentration. KBrO_3-induced methaemoglobinemia, renal oxidative stress and kidney damage, consequently, seemed to result from the attenuation of GPx activity. Besides, the enhancement of NO production was not likely to be a result but a cause for the KBrO_3-induced attenuation of GPx activity. In in vitro experiments, oxidation of human oxyhaemoglobin (HbO_2) to MetHb was observed in a reaction mixture containing HbO_2 and an NO donor, NOC-7 (1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene) or SIN-1 (3-(4-morpholinyl)sydnonimine), and this oxidation was inhibited by the NO scavenger carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylim-idazoline-1-oxyl 3-oxide). However, no MetHb formation was observed in a reaction mixture containing HbO_2 and KBrO_3. These results suggest that KBrO_3-induced methaemoglobinemia results from the reduction of GPx activity in blood by the KBrO_3-induced increases in superoxide, NO and ONOO.
公益社団法人日本薬学会の論文
2002-10-01

Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood(Toxicology)

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